Chiral resolution of an intermediate of suvorexant and cocrystals thereof

ABSTRACT

Relating to processes for preparing suvorexant or its pharmaceutically acceptable salts through the formation of a cocrystal of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloride with (R)-(+)-1,1,2-triphenyl-1,2-ethanediol ((R)-TED). This cocrystal provides the resolution of an intermediate of suvorexant, in particular, of (rac)-benzyl5-methyl-1,4-diazepane-1-carboxy-lateor a hydrochloride salt thereof. It also relates to a new cocrystal useful in such preparation processes.

This application claims the benefit of European Patent ApplicationEP16382260.4 filed 6 Jun. 2016.

TECHNICAL FIELD

The present invention relates to processes for preparing suvorexant orits salts through the resolution of (rac)-benzyl5-methyl-1,4-diazepane-1-carboxylate which is an intermediate ofsuvorexant. It also relates to new cocrystals useful in such preparationprocesses.

BACKGROUND ART

Suvorexant (MK-4305) is the International Non-proprietary Name (INN) of[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanoneand its CAS number is 1030377-33-3. It is currently marketed as Belsomraand is a selective, dual orexin receptor antagonist for the treatment ofinsomnia.

The structure of suvorexant corresponds to formula (I) below.

Suvorexant has one chiral center with a configuration (R). The synthesisof suvorexant is described in the patent family of WO2008069997A1 and inCox et al., J. Med. Chem. 2010, vol. 53, pp. 5320-5332. In particular, asynthesis that is based on a chiral stationary phase HPLC resolution ofa racemic 1,4-diazepane derivative ((rac)-(VIIIa)) is described (seescheme 1).

However, the chiral resolution of enantiomers of the 1,4-diazepanederivative ((rac)-(VIIIa)) via chiral HPLC is not adapted to anindustrial process and has several drawbacks: moderate throughput, largeamount of solvent, high cost, and large amount of waste.

In WO2016020404A1, the resolution of different possible intermediates ofsuvorexant is disclosed based on the formation of diastereomeric saltswith tartaric acid derivatives such as 2,3-ditoluoyl tartaric acid,2,3-dibenzoyl tartaric acid, 2,3-dianisoyl tartaric acid, and2,3-dibenzoyl tartaric acid mono(dimethylamide). Amongst these possibleintermediates, resolution of (rac)-(III) was performed by formation of adiastereomeric salt with 2,3-dibenzoyl D-tartaric acid (DBTA) (seeScheme 2).

Two examples of resolution of (rac)-benzyl5-methyl-1,4-diazepane-1-carboxylate with DBTA were described (see page69-70 of WO2016020404A1). One on a small scale (1.25 g) wherecrystallization of (rac)-benzyl 5-methyl-1,4-diazepane-1-carboxylatewith DBTA (1 eq.) in acetone afforded benzyl5-methyl-1,4-diazepane-1-carboxylate.DBTA salt with 18% yield and 93.4%ee (enantiomeric excess). Another at larger scale (7.26 g) wherecrystallization of (rac)-benzyl 5-methyl-1,4-diazepane-1-carboxylatewith DBTA (0.5 eq.) in acetone afforded benzyl5-methyl-1,4-diazepane-1-carboxylate.DBTA salt with a higher yield of31% but a lower 76.6% ee. The recrystallization of this last compound inethanol afforded the compound with 64% yield and 95.4% ee. The globalyield to obtain the compound with 95.4% ee is 19.8%. Thus, in bothexamples, (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate.DBTA wasobtained with a low yield (18-19%) and with <96% ee. As the enantiomericexcess of these examples remains low, one or more additionalrecrystallizations should be performed to reach 98-99% ee, decreasingeven further the low yield of this resolution.

Hence, there is the need to provide an efficient method for theresolution of (rac)-benzyl 5-methyl-1,4-diazepane-1-carboxylate, whichis an intermediate of suvorexant, with improved yield and higher % ee.

SUMMARY OF THE INVENTION

The inventors have developed a process for the resolution of(rac)-benzyl 5-methyl-1,4-diazepane-1-carboxylate ((rac)-(III)), or asalt thereof, such as the hydrochloride salt, by formation of acocrystal of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride with (R)-(+)-1,1,2-triphenyl-1,2-ethanediol ((R)-TED).

According to the inventors' knowledge, the use of cocrystals for theresolution of suvorexant intermediates has not been disclosed in theprior art. The identification of a cocrystal for use as a resolutionagent is not a routine exercise and the formation of a cocrystal cannotbe predicted theoretically. Other chiral 1,2-diols were also tested bythe inventors without success. Thus, the formation of a cocrystal of(R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(R)-TED, of formula (II) is considered a contribution to the art.

Accordingly, an aspect of the present invention relates to a cocrystalof (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(R)-TED, of formula (II) wherein Cbz is benzyloxycarbonyl, which has amolar ratio of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride: (R)-TED of 1:1.

Another aspect of the present invention relates to a resolution processcomprising the preparation of a cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride ((R)-(III).HCl) with(R)-TED, of formula (II) wherein Cbz is benzyloxycarbonyl, by a processwhich comprises: a₁) combining a_(1a)) either a mixture of ahydrochloride salt of (rac)-benzyl 5-methyl-1,4-diazepane-1-carboxylateof formula (rac)-(III) and (R)-TED or, alternatively, a_(1b))(rac)-benzyl 5-methyl-1,4-diazepane-1-carboxylate of formula(rac)-(III), (R)-TED, and hydrochloric acid; in a solvent selected fromthe group consisting of acetonitrile, isopropanol, ethyl acetate,acetone, tetrahydrofuran, tert-butyl methyl ether, and toluene; a₂)either heating the mixture until complete dissolution or, alternatively,slurrying between room temperature and reflux; a₃) cooling down thismixture, if necessary; and a₄) isolating the cocrystal of steps a₂) ora₃) thus obtained.

The cocrystal obtained in step a₂) or a₃) is the cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with (R)-TED offormula (II).

In a particular embodiment, of the previous process, the salt is thehydrochloride salt.

The previous process allows performing the resolution of (rac)-benzyl5-methyl-1,4-diazepane-1-carboxylate of formula (rac)-(III) or a saltthereof. The process may comprise converting the cocrystal of step a₄)into (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate or a salt thereof.

The resolution process of (rac)-benzyl5-methyl-1,4-diazepane-1-carboxylate or a salt thereof, in particular ofa hydrochloride salt thereof, may comprise: a) preparing a cocrystal of(R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(R)-TED of formula (II) by the process disclosed above, optionallypurifying the cocrystal thus obtained by either recrystallization or byslurrying in an organic solvent, and b) dissociating the cocrystal thusobtained to yield (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride salt, if desired converting it to its free base of formula(R)-(III); and, if desired, c) converting the resulting free base into asalt thereof by reacting it with an acceptable acid.

The previous process when comprising one recrystallization affords veryhigh % ee (>99% ee with only one recrystallization) with a satisfactoryyield around 25-30%. Furthermore, the same solvent can be used for twoof the steps of the resolution process (formation of the cocrystal forinstance by crystallization, and then recrystallization). An additionaladvantage is the easy recovery of TED during the dissociation step. Theresolution process may be carried out from (rac)-benzyl5-methyl-1,4-diazepane-1-carboxylate or a hydrochloride salt thereof orfrom a mixture of (R) and (S) enantiomers of any of these compounds inother ratios.

Another aspect of the present invention relates to the use of thecocrystal of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride with (R)-TED, of formula (II) as defined above, as anintermediate for the preparation of (R)-suvorexant or a pharmaceuticallyacceptable salt thereof.

Also part of the invention are processes for preparing suvorexant offormula (I), or a pharmaceutically acceptable salt thereof, whichcomprise a) carrying out the resolution process as disclosed above, andconverting the compound thus obtained into suvorexant or itspharmaceutically acceptable salts by methods disclosed in the state ofthe art which are disclosed in detail below. These processes have betterindustrial applicability and utility than the known processes forpreparing suvorexant and overcome the drawbacks of the existing ones.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the XRPD of the cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate.HCl with (R)-TED named Form A.

FIG. 2 shows the ¹H NMR of Form A.

FIG. 3 shows the DSC of Form A.

FIG. 4 shows the TGA of Form A

DETAILED DESCRIPTION OF THE INVENTION

For the sake of understanding, the following definitions are includedand expected to be applied throughout the description, claims anddrawings.

Unless stated otherwise, the term “suvorexant” in the context of thepresent invention relates to (R)-suvorexant. Both terms have been usedinterchangeably.

The term “cocrystal” refers herein to a crystalline entity with at leasttwo different components constituting the unit cell at room temperature(20-25° C.) and interacting by weak interactions. Thus, in a cocrystalthe target molecule crystallizes with one or more neutral components.The cocrystals may include one or more solvent molecules in the crystallattice.

The term “weak interaction” refers herein as an interaction which isneither ionic nor covalent, and includes for example: hydrogen bonds,van der Waals interactions, and π-π stacking.

When a ratio of components of the cocrystals of the invention isspecified it refers to the molar ratio between the two components thatform the cocrystal. The term “molar ratio” has been used to express thestoichiometric amount in moles of each of the components of a cocrystal.

When values of characteristic peaks of an X-ray diffractogram are givenit is said that are “approximate” values. It should be understood thatthe values are the ones shown in the corresponding lists or tables ±0.3degrees 2 theta measured in an X-ray diffractometer with Cu—K_(α)radiation λ=1.5406 Å.

The term “room temperature” as disclosed herein refers to a temperatureof the environment, without heating or cooling, and is generallycomprised of from 20 to 25° C.

For the purposes of the invention, any ranges given include both thelower and the upper end-points of the range. Ranges given, such astemperatures, times and the like, should be considered approximate,unless specifically stated.

Enantiomeric excess (ee) is a measurement of purity used for chiralsubstances. It reflects the degree to which a sample contains oneenantiomer in greater amounts than the other. The term “enantiomericpurity” (or optical purity) is defined as the fractional excess of oneenantiomer over the other.

The expression “cocrystal obtainable by” is used here to define eachspecific cocrystal of the invention by the process for obtaining it andrefers to the product obtainable by any of the corresponding processesdisclosed herein. For the purposes of the invention the expressions“obtainable”, “obtained” and equivalent expressions are usedinterchangeably and, in any case, the expression “obtainable”encompasses the expression “obtained”.

The terms “wet grinding” and “liquid assisted grinding” are equivalentand refer to a technique which consists of milling or grinding theproduct or mixture with some drops of solvent added. Neat andliquid-assisted grinding are techniques that can be employed in order toproduce cocrystals. In neat (dry) grinding, cocrystal formers are groundtogether manually using a pestle and mortar, using a ball mill, or usingan oscillatory mill. In liquid-assisted grinding, or kneading, a smallamount of liquid (solvent), for instance, some drops of liquid, is addedto the grinding mixture.

As mentioned above, part of the invention is the provision of acocrystal of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride with (R)-(+)-1,1,2-triphenyl-1,2-ethanediol ((R)-TED), offormula (II), which has a molar ratio of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride:(R)-(+)-1,1,2-triphenyl-1,2-ethanediol of 1:1.

In formula (II), Cbz represents the benzyloxycarbonyl group.

In a preferred embodiment, the cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with (R)-TED, offormula (II), is a crystalline form named Form A. This cocrystal Form Ais easy to handle and shows crystal stability at room temperature.

The specific crystalline forms of the cocrystals of the presentinvention can be characterized by X-ray powder diffraction (XRPD),proton nuclear magnetic resonance analyses (¹H NMR), differentialscanning calorimetry (DSC), and thermogravimetric analysis (TGA).

Diffraction measurements were performed at ambient conditions on aPANalyticalX'Pert PRO diffractometer with reflection θ-θ geometry,equipped with Cu K-alpha radiation and a PIXcel detector, operated at 45kV and 40 mA. Each powder was mounted on a zero background siliconholder and allowed to spin during the data collection at 0.25 rev/s. Themeasurement angular range was 3.0-40.0° (2θ) with a step size of 0.013°.The scanning speed was 0.32826°/s.

Proton and carbon nuclear magnetic resonance analysis were recorded indeuterated chloroform in a Varian Mercury 400 spectrometer, equippedwith a broadband probe ATB 1H/19F/X of 5 mm. Spectra were acquireddissolving 5-10 mg of sample in 0.6 mL of deuterated solvent.

DSC analysis was recorded with a Mettler DSC2. A sample of 2.4900 mg wasweighed into a 40 μL aluminium crucible with a pinhole lid and washeated, under nitrogen (50 mL/min), at 10° C./min from 25 to 300° C.

Thermogravimetric analysis (TGA) was recorded in a Mettler TGA/SDTA851ethermogravimetric analyzer. A sample of 4.3400 mg was weighed into a 100μL aluminium crucible and sealed with a lid. Samples were heated at 10°C./min from 25 to 550° C., under nitrogen (50 mL/min).

In a preferred embodiment, Form A of the cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with (R)-TED, offormula (II), is characterized by having an X-ray diffractogram thatcomprises characteristic peaks at approximately 5.3, 10.6 and 15.8degrees 2 theta at a Cu—K_(α) radiation, λ=1.5406 Å. In a more preferredembodiment, this cocrystal is characterized by further comprisingcharacteristic peaks in the X-ray powder diffractogram at approximately9.8, 12.9, and 19.7 degrees 2 theta at a Cu—K_(α) radiation, λ=1.5406 Å.In a still more preferred embodiment, this cocrystal is characterized byfurther comprising characteristic peaks in the X-ray powderdiffractogram at approximately 6.5, 15.3, 15.8, 19.4, and 22.4 degrees 2theta at a Cu—K_(α) radiation, λ=1.5406 Å.

More specifically, this new cocrystal Form A is characterized byexhibiting in the X-ray powder diffractogram a pattern of peaks,expressed in 2 theta units in degrees, 2θ (°), which is shown in Table1.

TABLE 1 List of selected peaks (only peaks with relative intensitygreater than or equal to 1% are indicated): Pos. [°2Th.] d-spacing [Å]Rel. Int. [%] 5.3 16.6 00 6.4 13.8 52 6.5 13.6 39 9.9 9.0 10 10.6 8.3 4211.9 7.5 11 12.9 6.9 74 13.0 6.8 31 14.5 6.1 10 15.3 5.8 45 15.8 5.6 3917.5 5.1 30 18.0 4.9 42 18.7 4.8 26 19.4 4.6 35 19.8 4.5 23 20.5 4.3 2920.6 4.3 26 21.4 4.2 85 22.4 4.0 72 23.1 3.9 7 23.8 3.7 10 24.3 3.7 3125.7 3.5 47 26.5 3.4 20 28.4 3.1 22 28.6 3.1 18 29.0 3.1 6 29.6 3.0 930.5 2.9 5 30.8 2.9 4 31.9 2.8 2 32.7 2.7 4 33.4 2.7 4 34.2 2.6 6 35.22.6 3 35.8 2.5 4 37.5 2.4 2 39.4 2.3 2

This cocrystal Form A may be further characterized by an X-raydiffractogram as in FIG. 1.

This cocrystal Form A may also be further characterized by the following¹H NMR spectrum 1H NMR (CDCl₃, 400 MHz): δ=9.78 (s br, 2H), 7.73-7.67(m, 2H arom.), 7.43-7.27 (m, 8H arom.), 7.21-7.03 (m, 10H arom.),5.66-5.62 (m, 1H), 5.19-5.09 (m, 2H, Ph-CH₂—CO), 4.06-3.89 (m, 1H),3.79-3.49 (m, 3H), 3.46-3.25 (m, 2H), 3.16 (s, 1H, −OH) 3.12-2.90 (m,1H), 2.52 (d, 1H, —OH), 2.33-2.18 (m, 1H), 2.15-1.97 (m, 1H), 1.57-1.51(m, 3H, —CH₃). This cocrystal Form A may be further characterized by a¹H NMR spectrum as in FIG. 2.

The cocrystal Form A may also be further characterized by an endothermicsharp peak corresponding to the melting point with an onset at about152° C. (fusion enthalpy −107.89 J/g) measured by DSC analysis. Thiscocrystal Form A may be further characterized by DSC analysis as in FIG.3.

The ratio (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate.HCl: (R)-TEDin the cocrystal may be determined by ¹H NMR, titration, or elementalanalysis.

A preliminary process which was used for the preparation of a cocrystalof (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(R)-TED, of formula (II), as defined above, comprises: wet grinding:either a) a mixture of a hydrochloride salt of (rac)-benzyl5-methyl-1,4-diazepane-1-carboxylate of formula (rac)-(III) and (R)-TED;or alternatively, b) a mixture of (rac)-benzyl5-methyl-1,4-diazepane-1-carboxylate, (R)-TED, and hydrochloric acid; ina solvent selected from the group consisting of acetonitrile,isopropanol, ethyl acetate, acetone, tetrahydrofuran, tert-butyl methylether; dichloromethane and toluene. In a particular embodiment, thesolvent used is acetonitrile.

As mentioned above, part of the invention is a process for preparing acocrystal of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride with (R)-TED of formula (II) which comprises: a) combiningeither a_(1a)) a mixture of a hydrochloride salt of (rac)-benzyl5-methyl-1,4-diazepane-1-carboxylate of formula (rac)-(III) and (R)-TED,or alternatively, a_(1b)) (rac)-benzyl5-methyl-1,4-diazepane-1-carboxylate of formula (rac)-(III), (R)-TED,and hydrochloric acid; in a solvent selected from the group consistingof acetonitrile, isopropanol, ethyl acetate, acetone, tetrahydrofuran,tert-butyl methyl ether and toluene; _(a2)) either heating the mixtureuntil complete dissolution or slurrying between room temperature andreflux; a₃) cooling down this mixture, if necessary; a₄) isolating thecocrystal of steps a₂) or a₃) thus obtained.

Since the hydrochloric acid may be aqueous hydrochloric acid, thesolvent system may be a mixture of any of the solvents mentioned above(acetonitrile, isopropanol, ethyl acetate, acetone, tetrahydrofuran,tert-butyl methyl ether; and toluene) with water, preferably ACN andwater. In particular, the amount of water in the mixture ofsolvent/water may be comprised up to 10% v/v. In a particularembodiment, the amount of water is comprised between 5-10% v/v.

In a particular embodiment, the solvent used is acetonitrile. In anotherparticular embodiment, the cocrystal is obtained by slurrying inacetonitrile. In another particular embodiment, the cocrystal isobtained by crystallization from acetonitrile. Thus, a hot solution,preferably at reflux temperature is slowly cooled down to crystallizethe cocrystal. The solution can be seeded to facilitate thecrystallization.

(rac)-Benzyl 5-methyl-1,4-diazepane-1-carboxylate ((rac)-(III)) can beprepared using the methods described in Cox et al., J. Med. Chem. 2010,53, 5320-5332 or in WO2008069997A1 (see scheme E of this patentapplication). The (rac)-(III) thus obtained can be transformed into itshydrochloride salt by known methods, for instance, by reacting it withhydrochloric acid in an appropriate solvent. (R)-TED is commerciallyavailable (CAS number 95061464) and can also be easily and economicallyobtained from mandelic acid which is a cheap raw material by methodsknown in the art.

The cocrystals of the present invention may be purified byrecrystallization. Thus, after its preparation, a cocrystal can besubmitted to a further recrystallization. In a preferred embodiment, theresolution process further comprises one recrystallization step. In aparticular embodiment, the cocrystal of the present invention is Form A.

They can also be submitted to a slurrying process. In both cases(recrystallization or slurrying) the solvent is selected from the groupconsisting of acetonitrile, isopropanol, ethyl acetate, acetone andtoluene. In a particular embodiment, the solvent used is acetonitrile.The same solvent can be used for the preparation step and for therecrystallization step or for the slurrying step.

In a preferred embodiment, Form A of the cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with (R)-TED offormula (II) is prepared using acetonitrile as solvent.

The cocrystal of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride with (R)-TED of the invention may also be defined by itspreparation process. Accordingly, this aspect of the invention can beformulated as cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with (R)-TED, asdefined above, obtainable by the process disclosed above, optionallyincluding any preferred or particular embodiments of the process, andpossible combinations of some of the process features disclosed above.

The use of a cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with (R)-TED, offormula (II), as an intermediate for the preparation of (R)-suvorexantor a pharmaceutically acceptable salt thereof is also part of theinvention. Suvorexant may be obtained with ≥99% ee. The cocrystals ofthe present invention allow the resolution of a key intermediate in thepreparation of suvorexant.

Accordingly, the resolution process of (rac)-benzyl5-methyl-1,4-diazepane-1-carboxylate or a hydrochloride salt thereof isalso part of the invention and comprises: a) preparing a cocrystal of(R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(R)-TED), of formula (II), by the process disclosed above, optionally,either recrystallizing or slurrying the cocrystal thus obtained; and b)dissociating the cocrystal thus obtained to yield (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride salt, if desired,converting the salt into its free base of formula (R)-(III) and, ifdesired, converting the resulting free base into a salt thereof byreacting it with an appropriate acid.

In a preferred embodiment, the resolution process is carried out fromracemic benzyl 5-methyl-1,4-diazepane-1-carboxylate free base asstarting material. In another preferred embodiment, the resolutionprocess is carried out from the hydrochloride salt of racemic benzyl5-methyl-1,4-diazepane-1-carboxylate as starting material.

In a particular embodiment of the resolution process, the dissociationstep comprises: (1) slurrying the cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with (R)-TED, offormula (II), in water at room temperature; (2) separating the (R)-TEDfrom the medium; and (3) basifying the aqueous phase, and extracting the(R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate with an appropriateorganic solvent. The solution thus obtained may be used; directly forthe next step. Alternatively, the (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate free base can be isolated from thesolution. As an example, the combined organic phases may be concentratedto dryness under vacuum at room temperature affording (R)-(III) freebase as a colorless oil. If desired, a salt of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate free base may be prepared byreacting the free base with an appropriate acid.

The aqueous phase which contains the (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride salt may be basified,for instance, with sodium hydroxide 1 M (pH 12), and may be extractedwith, for instance, dichloromethane, preferably twice.

In another particular embodiment, the dissociation step comprises: (1)slurrying the cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with (R)-TED, offormula (II), in water at room temperature; (2) separating the (R)-TEDfrom the medium; and (3) concentrating the aqueous phase to isolate the(R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloride salt.

When the cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate.HCl with (R)-TED, Form A, isdissociated by slurrying in water at room temperature, the (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride remains dissolved inwater and (R)-TED, insoluble in water, crystallizes. The crystalline(R)-TED may be recovered from the reaction medium, for instance, byfiltration or by extraction in an organic solvent.

The enantiomeric excess of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate free base can be determined asexplained in the Examples section. The results show that the process ofthe present invention (see, for instance Examples 4, 5 and 8) can afforda higher global yield than the resolution method described inWO2016020404A1 (up to 30% instead of 20%) with an excellent enantiomericexcess (>99% ee instead of 96% ee).

The other enantiomer (S)-(III) or its hydrochloride salt can be resolvedin the same way using the other enantiomer of TED, i.e. (S)-TED. It hasthe same X-ray, DSC and TGA as its enantiomer.

The chirality of each of the compounds can be determined as illustratedin Example 9.

The (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate (R)-(III) or itssalts as defined above and obtained by the process of the invention, maybe easily converted into suvorexant or its pharmaceutically acceptablesalts by methods known in the art. Two different approaches can befollowed for this conversion.

One approach involves a) N-acylation of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate (R)-(III) or its salts with abenzoic acid derivative of formula (IV) wherein X is OH or Cl; b)N-deprotection to provide compound (VI); and c) coupling with abenzoxazole derivative compound (VII). This approach is applied, forinstance, in WO20080699997 or in J. Med. Chem. 2010, 53, 5320-5332.

Accordingly, also part of the invention is a process for preparingsuvorexant of formula (I) or a pharmaceutically acceptable salt thereof,which comprises: a) carrying out the resolution process as definedabove, b) N-acylating the compound of formula (R)-(III) thus obtainedwith a benzoic acid derivative of formula (IV) wherein X is OH or CI, toyield a compound of formula (V); c) deprotecting the amino group of thecompound of formula (V) thus obtained to provide a compound of formula(VI); d) coupling the compound obtained in step c) with a benzoxazolederivative of formula (VII) wherein Y is H, Cl or Br; to yieldsuvorexant (I) or a pharmaceutically acceptable salt thereof; and e) ifdesired, converting the resulting suvorexant free base into apharmaceutically acceptable salt thereof by reacting it with anacceptable acid.

Step b) of the previous process may be carried out in the presence of abase, particularly, when the starting material is (R)-(III)hydrochloride salt. Examples of appropriate bases are: tertiary amines(eg. triethylamine or diisopropylethylamine) or inorganic bases (eg.alkali metal carbonates such as potassium carbonate).

When in compound of formula (IV) X is OH, the coupling can be effectedwith coupling agents well known to a person skilled in the art.

Example procedures for carrying out the coupling where Y is H, Cl or Brcan be found in WO2015008218, WO2008069997 and WO2013169610,respectively.

This approach is illustrated in the following scheme:

In the formula (R)-(III) and (V) Cbz means benzyloxycarbonyl.

Another approach encompasses the N-protection of the compound (R)-(III)as defined above with an orthogonal protecting group PG, followed byN-Cbz cleavage. Then, suvorexant can be obtained by a process involvinga) coupling with a benzoxazole derivative of formula (VII); b)N-deprotection to provide compound (XI); and c) coupling with a benzoicacid derivative (IV). Aspects of this approach are applied, forinstance, in WO2016020404A1, WO2015008218A2 and WO2012148553A1 where Xand Y are defined as described above.

Accordingly, also part of the invention is a process for preparingsuvorexant of formula (I) or a pharmaceutically acceptable salt thereof,which comprises: a) carrying out the resolution process disclosed above,b) N-protecting a compound of formula (R)-(III) thus obtained with anorthogonal protecting group PG (i.e. a protecting group which can beremoved selectively in the presence of Cbz) to yield a compound offormula (VIII); c) cleavage of Cbz protecting group to yield a compoundof formula (IX); d) coupling the compound thus obtained with abenzoxazole derivative of formula (VII) wherein Y is H, CI or Br toyield a compound of formula (X); e) N-deprotecting the compound offormula (X) to yield a compound of formula (XI); f) coupling thecompound of formula (XI) with a benzoic acid derivative of formula (IV)where X is OH or Cl (coupling where X=OH can be effected with couplingagents well known to a person skilled in the art), to yield suvorexantor a pharmaceutically acceptable salt thereof; and, if desired, g)converting the resulting suvorexant free base into a pharmaceuticallyacceptable salt thereof by reacting it with a pharmaceuticallyacceptable acid.

Step b) of the previous process may be carried out in the presence of abase, particularly, when the starting material is (R)-(III)hydrochloride salt. Examples of appropriate bases are: tertiary amines(eg. triethylamine or diisopropylethylamine) or inorganic bases (eg.alkali metal carbonates such as potassium carbonate).

This approach is illustrated in the following scheme:

In a particular embodiment of the processes for the preparation ofsuvorexant disclosed above X in compound (IV) is chlorine. In anotherparticular embodiment of the processes for the preparation ofsuvorexant, Y in compound (VII) is bromine or chlorine.

The deprotection of the Cbz group can be carried out, for instance byhydrogenolysis with H₂, Pd(OH)₂, EtOAc. This amino protective group canbe introduced and removed by other procedures known in the art (cf. T.W. Greene and G. M. Wuts, Protective Groups in Organic Synthesis, ThirdEdition, Wiley, N.Y., 1999, see pages 531-535).

The group PG is a suitable orthogonal amino protecting group. The term“suitable orthogonal amino protecting group” as used herein is denotedto encompass any amino protecting group other than the protective groupCbz used to protect the other amino group of compound of formula(R)-(III), stable to selected Cbz cleavage conditions (for example,hydrogenolysis). Representative protecting groups for amino groups arewell known to those skilled in the art and are described, for example,in T. W. Greene and G. M. Wuts, Protective Groups in Organic Synthesis,Third Edition, Wiley, N.Y., 1999 (see chapter 7). Preferred protectinggroups for PG include, but are not limited to, carbamate-forming groupssuch as Boc (tert-butyloxycarbonyl), Fmoc(9-fluorenylmethyloxycarbonyl), methyl and ethyl carbamates;sulfonamide-forming groups such as tosyl; and amide-forming groups suchas formyl, (un)substituted acetyl, and benzoyl. In a preferredembodiment, PG is Boc.

The coupling of compound (IX) with compound (VII, Y=Cl or Br) and thecoupling of compound of formula (XI) with a benzoic acid derivative offormula (IV, X=Cl) can be carried out, for instance, in the presence ofa base, such as triethylamine, and an appropriate solvent such asdichloromethane.

The coupling of compound (IX) with compound (VII, Y=H) can be carriedout, for instance, in the presence of Cu(OAc)₂ in acetic acid andacetonitrile according to WO2015008218A2.

The coupling of compound (XI) with a benzoic acid derivative of formula(IV, X=OH) can be carried out in the presence of standard amide-formingcoupling reagents known to a person expert in the art.

The term “pharmaceutically acceptable salts” refers to salts prepared bymethods known in the art from pharmaceutically acceptable non-toxicacids including inorganic or organic acids. Such acids include acetic,benzene sulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, orp-toluenesulfonic acid.

Throughout the description and claims the word “comprise” and variationsof the word, are not intended to exclude other technical features,additives, components, or steps. Furthermore, the word “comprise”encompasses the case of “consisting of”. Additional objects, advantagesand features of the invention will become apparent to those skilled inthe art upon examination of the description or may be learned bypractice of the invention. The following examples and drawings areprovided by way of illustration, and they are not intended to belimiting of the present invention. Furthermore, the present inventioncovers all possible combinations of particular and preferred embodimentsdescribed herein.

EXAMPLES Example 1: Detection of the Cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(R)-(+)-1,1,2-triphenyl-1,2-ethanediol Form A and of the Cocrystal of(S)-benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(S)-(−)-1,1,2-triphenyl-1,2-ethanediol

The starting materials used are (rac)-benzyl5-methyl-1,4-diazepane-1-carboxylate.HCl and (R)-TED (1:1) or (S)-TED(1:1).

A cocrystal of (S)-benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride with (S)-(−)-1,1,2-triphenyl-1,2-ethanediol was obtainedby both slurrying and by wet grinding in acetonitrile (ACN).

A cocrystal of (S)-benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride with (S)-(−)-1,1,2-triphenyl-1,2-ethanediol was alsoobtained by slurrying with isopropanol, ethyl acetate, acetone andtoluene as solvent and also by wet grinding with isopropanol, ethylacetate, acetone, tetrahydrofuran, tert-butyl methyl ether,dichloromethane and toluene.

The cocrystal of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride with (R)-(+)-1,1,2-triphenyl-1,2-ethanediol Form A may beobtained by slurrying and by grinding in ACN (rac)-benzyl5-methyl-1,4-diazepane-1-carboxylate.HCl with (R)-TED (1:1).

The cocrystal of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride with (R)-(+)-1,1,2-triphenyl-1,2-ethanediol Form A mayalso be obtained by slurrying with isopropanol, ethyl acetate, acetone,and toluene as solvent and also by wet grinding with isopropanol, ethylacetate, acetone, tetrahydrofuran, tert-butyl methyl ether,dichloromethane, and toluene.

Example 2: Preparation of a Cocrystal of (S)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(S)-(−)-1,1,2-triphenyl-1,2-ethanediol and of the Cocrystal of(R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(R)-(+)-1,1,2-triphenyl-1,2-ethanediol Form A by slurrying inacetonitrile (ACN)

In an Eppendorf, racemic benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride (19.8 mg, 0.07 mmols) and(S)-1,1,2-triphenyl-1,2-ethandiol (20.1 mg, 0.07 mmols) were suspendedin acetonitrile (0.2 mL). The resulting suspension was left stirring atroom temperature for 15 hours (overnight). Then, the solid was recoveredby centrifuge and dried under high vacuum at room temperature.

(R)-Benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(R)-(+)-1,1,2-triphenyl-1,2-ethanediol Form A may be obtained by thesame process starting from (R)-1,1,2-triphenyl-1,2-ethandiol instead of(S)-1,1,2-triphenyl-1,2-ethandiol.

Example 3: Preparation of a Cocrystal of (S)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(S)-(−)-1,1,2-triphenyl-1,2-ethanediol and of the Cocrystal of(R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(R)-(+)-1,1,2-triphenyl-1,2-ethanediol Form A by wet grinding in ACN

In an Eppendorf, (rac)-benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride (20.3 mg, 0.07 mmols), (S)-1,1,2-triphenyl-1,2-ethandiol(20.2 mg, 0.07 mmols), two drops of acetonitrile and three steel ballswere combined. The resulting mixture was milled three times for 10minutes at 30 MHz in a grinding mortar and the solid was dried underhigh vacuum at room temperature.

(R)-Benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(R)-(+)-1,1,2-triphenyl-1,2-ethanediol Form A may be obtained by thesame process starting from (R)-1,1,2-triphenyl-1,2-ethandiol instead of(S)-1,1,2-triphenyl-1,2-ethandiol.

Example 4: Preparation of the Cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(R)-(+)-1,1,2-triphenyl-1,2-ethanediol, of Formula (II), Form A, byCrystallization from ACN

In a round-bottomed 10 mL flask, (rac)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride (1 g, 3.52 mmol) and(R)-1,1,2-triphenyl-1,2-ethandiol (1.027 g, 3.53 mmol, 1.0 equiv.) weresuspended in acetonitrile (6.0 mL). The resulting mixture was heated toreflux. The resulting clear solution was stirred for 10 min at refluxbefore cooling slowly to room temperature. During the cooling, themixture was seeded by Form A each 10° C. and a white solid started tocrystallize at 60° C. Once at room temperature, the resulting suspensionwas stirred 3 h at room temperature and 1 h at 0-5° C. with an ice bathbefore isolating the solid. The white solid was filtered in a sinteredfunnel (no. 3), washed twice with cold acetonitrile (2×1.0 mL) and driedunder high vacuum at room temperature to provide Form A (835 mg, 41%yield, 88% ee) as a white solid.

Example 5: Recrystallization of the Cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(R)-(+)-1,1,2-triphenyl-1,2-ethanediol Form A from ACN

In a round-bottomed 10 mL flask equipped with magnetic stirring, thecocrystal of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride with (R)-(+)-1,1,2-triphenyl-1,2-ethanediol Form A (801.4mg, 1.39 mmol, 88% ee) was suspended in acetonitrile (4.8 mL). Theresulting mixture was heated to reflux. The resulting clear solution wasstirred for 10 min at reflux before cooling slowly to room temperature.During the cooling, the mixture was seeded by Form A each 10° C. and awhite solid started to crystallize at 60° C. Once at room temperature,the resulting suspension was stirred 3 h at room temperature and 1 h at0-5° C. with an ice bath before isolating the solid. The white solid wasfiltered in a sintered funnel (no. 3), washed twice with coldacetonitrile (2×0.8 mL) and dried under high vacuum at room temperatureto provide Form A (639 mg, 80% yield, >99% ee) as a white solid.

Seeding crystals may be obtained by any of the processes disclosedabove. They can additionally be obtained from the wet grinding processdisclosed above but using (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate of formula (R)-(III) as startingmaterial.

Example 6: Crystallization of the Cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(R)-(+)-1,1,2-triphenyl-1,2-ethanediol Form A and of the Cocrystal of(S)-benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(S)-(−)-1,1,2-triphenyl-1,2-ethanediol from ACN

Several assays were carried out crystallizing the cocrystals in 7 vol.ACN in the conditions shown in Table 1.

TABLE 1 Exp. TED Eq.-TED Scale Yield % ee 6A S 1 100 mg 33% 84 6B S 2100 mg 43% 79 6C S 1 500 mg 41% 75 6D R 1 500 mg 39% 81 6E R 1  1 g 41%87

Example 7: Recrystallization of the Cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(R)-(+)-1,1,2-triphenyl-1,2-ethanediol Form A and of the Cocrystal of(S)-benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloride with(S)-(−)-1,1,2-triphenyl-1,2-ethanediol from ACN

Several assays were carried out recrystallizing the cocrystal in 6 vol.ACN in the conditions shown in Table 2.

TABLE 2 Exp. From Scale Yield % ee 7A 6A (84% ee)  50 mg 52% >99 7B 6B(79% ee)  50 mg 52% >99 7C 6C (75% ee) 400 mg 59% >99 7D 6D (81% ee) 350mg 74% >99 7E 6E (87% ee) 800 mg 80% >99

Example 8: Preparation of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate Free Base by Dissociation of theCocrystal of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride with (R)-(+)-1,1,2-triphenyl-1,2-ethanediol Form A

In a round-bottomed 10 mL flask equipped with magnetic stirring, Form A(94 mg, 0.164 mmols, >99% ee) was suspended in cold water (2.0 mL) andstirred for 1 h at 0-4° C. in an ice bath. (R)-TED was filtered using asintered funnel (no. 3), washed twice with cold water (2×0.5 mL) anddried under high vacuum at room temperature affording(R)-1,1,2-triphenyl-1,2-ethandiol (44 mg, 92% recovery) as a whitecrystalline solid.

The combined aqueous mother liquor was washed with TBME (2×1 mL) beforeadding dichloromethane (3 mL) and a solution of 1 M sodium carbonateuntil pH 10. After a vigorous stirring, the phases were separated andthe aqueous phase was extracted twice with dichloromethane (2×3 mL). Thecombined organic phases were washed with water (3 mL) and brine (3 mL),and dried over anhydrous sodium sulphate. The solvent was distilled atroom temperature under vacuum to obtain (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate free base (40 mg, 84% yield, 99%ee) as a pale yellow oil.

Example 9: Determination of the Chiral Configuration of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate Free Base

The chiral configuration of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate free base was determined by:

a) Reproducing the resolution of (rac)-benzyl5-methyl-1,4-diazepane-1-carboxylate with DBTA described in the Sandozpatent (WO2016020404A1, see for instance from page 17 onwards and frompage 70 onwards), allowed comparison of (R)-III retention time by chiralHPLC analysis with that of Form A, and confirmed that (R)-TED forms acocrystal with (R)-III.HCl.

Analytical HPLC analyses were carried out on a Chiralpak IA column (5μm, 4.6 mm×250 mm) with a mixture of heptane/EtOH-0.2% DEA 90:10 aseluent and at a flow rate of 1 mL/min ((R)-III is the first elutingenantiomer—Tr (R)-III 12.0 min and (S)-III) 14.0 min).

b) Protecting the second amine of (R)-III free base with a Boc group,measuring the specific rotation ([α]_(D)−24.0 (c 1.10, chloroform)), andcomparing it to literature values ([α]_(D)−24.3 (c 1.0, chloroform),see. Cox et al., J. Med. Chem. 2010, vol. 53, pp. 5320-5332).

CITATION LIST Patent Literature

-   WO2008069997A1-   WO2016020404A1-   WO2015008218A2-   WO2012148553A1

Non Patent Literature

-   J. Med. Chem. 2010, vol. 53, pp. 5320-5332

1. A cocrystal of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylatehydrochloride with (R)-(+)-1,1,2-triphenyl-1,2-ethanediol ((R)-TED) offormula (II) wherein Cbz is benzyloxycarbonyl, which has a molar ratioof (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloride:(R)-(+)-1,1,2-triphenyl-1,2-ethanediol of 1:1.


2. The cocrystal according to claim 1, which is a crystalline form namedForm A, and is characterized by having an X-ray diffractogram thatcomprises characteristic peaks at approximately 5.3, 10.6, and 15.8degrees 2 theta at a Cu—K_(α) radiation, λ=1.5406 Å.
 3. The cocrystalaccording to claim 2, which is characterized by further comprisingcharacteristic peaks in the X-ray powder diffractogram at approximately9.8, 12.9, and 19.7 degrees 2 theta at a Cu—K_(α) radiation, λ=1.5406 Å.4. The cocrystal according to claim 3, characterized in that theendothermic sharp peak corresponding to the melting point has an onsetat about 152° C.
 5. A resolution process of (rac)-benzyl5-methyl-1,4-diazepane-1-carboxylate of formula (rac)-(III) or a saltthereof, which comprises a) preparing a cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with (R)-TED offormula (II) as defined in claim 1 by a process which comprises thesteps of: a₁) combining either a_(1a)) a mixture of a hydrochloride saltof (rac)-benzyl 5-methyl-1,4-diazepane-1-carboxylate of formula(rac)-(III) and (R)-(+)-1,1,2-triphenyl-1,2-ethanediol ((R)-TED) or,alternatively, a_(1b)) (rac)-benzyl 5-methyl-1,4-diazepane-1-carboxylateof formula (rac)-(III), (R)-TED and hydrochloric acid; in a solventselected from the group consisting of acetonitrile, isopropanol, ethylacetate, acetone, tetrahydrofuran, tert-butyl methyl ether and toluene;

a₂) either heating the mixture thus obtained until complete dissolutionor, alternatively, slurrying between room temperature and reflux; a₃)cooling down this mixture if necessary; and a₄) isolating the cocrystalof formula (II) obtained in steps a₂) or a₃); and b) converting thecocrystal obtained in step a₄) into (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate or a salt thereof.
 6. Theresolution process according to claim 5, further comprising arecrystallization step of the cocrystal obtained in step a₄) of claim 5,in a solvent selected from the group consisting of acetonitrile,isopropanol, ethyl acetate, acetone, and toluene.
 7. The resolutionprocess according to claim 5, wherein the solvent of the preparationstep is acetonitrile.
 8. The resolution process according to claim 5,wherein the solvent of the recrystallization step is acetonitrile. 9.The resolution process according to claim 5, wherein step b) comprisesdissociating the cocrystal to yield (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride salt, if desiredconverting the salt into its free base of formula (R)-(III) and, ifdesired, converting the compound thus obtained to a salt thereof byreacting it with an appropriate acid


10. The resolution process according to claim 9, wherein thedissociation step comprises: (1) slurrying the cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with (R)-TED offormula (II), in water between 0° C. and room temperature; (2)separating the (R)-TED from the medium; and (3) basifying the aqueousphase, extracting the (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate offormula (R)-(III) with an appropriate organic solvent; optionallyisolating the (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate of formula(R)-(III) as a free base, and if desired converting the free base into asalt thereof by addition of the corresponding acid.
 11. The resolutionprocess according to claim 9, wherein the dissociation step comprises:(1) slurrying the cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with (R)-TED offormula (II), in water between 0° C. and room temperature; (2)separating the (R)-TED from the medium; and (3) isolating the (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride of formula(R)-(III).HCl from the aqueous phase.
 12. A process for the preparationof (R)-suvorexant or a pharmaceutically acceptable salt thereof whichcomprises the use of the cocrystal of (R)-benzyl5-methyl-1,4-diazepane-1-carboxylate hydrochloride with (R)-TED offormula (II), as defined in claim 1, as an intermediate of the process.13. A process for preparing suvorexant of formula (I) or apharmaceutically acceptable salt thereof,

which comprises: a) carrying out the resolution process of claim 5 toyield (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate of formula(R)-(III) or a hydrochloride salt thereof, b) N-acylating a compound offormula (R)-(III), with a benzoic acid derivative of formula (IV)wherein X is OH or Cl, optionally in the presence of a base,

to yield a compound of formula (V);

wherein Cbz in compound (R)-(III) and (V) is benzyloxycarbonyl; c)deprotecting the amino group of the compound of formula (V) thusobtained to provide the compound of formula (VI);

d) coupling the compound obtained in step c) with a benzoxazolederivative of formula (VII) wherein Y is H, Cl or Br;

to yield suvorexant (I) or a pharmaceutically acceptable salt thereof;and e) if desired, converting the resulting suvorexant free base into apharmaceutically acceptable salt thereof by reacting it with apharmaceutically acceptable acid.
 14. A process for preparing suvorexantof formula (I) or a pharmaceutically acceptable salt thereof,

which comprises: a) carrying out the resolution process of claim 5, toyield (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate of formula(R)-(III) or a hydrochloride salt thereof, b) N-protecting a compound offormula (R)-(III) or its hydrochloride salt, optionally in the presenceof a base,

with an orthogonal protecting group PG, to yield a compound of formula(VIII)

c) cleavage of the Cbz group to yield a compound of formula (IX);

wherein PG is an amino protecting group; d) coupling the compound thusobtained with a benzoxazole derivative of formula (VII), wherein Y is H,Cl or Br,

to yield a compound of formula (X) wherein PG is an amino protectinggroup;

e) N-deprotecting the compound of formula (X) to yield a compound offormula (XI);

f) coupling the compound of formula (XI) with a benzoic acid derivativeof formula (IV) wherein X is OH or Cl,

to yield suvorexant or a pharmaceutically acceptable salt thereof and;if desired, g) converting the resulting suvorexant free base into a saltthereof by reacting it with a pharmaceutically acceptable acid.
 15. Theprocess according to claim 14, wherein PG is a tert-butoxycarbonylprotecting group.